Investigating the role of histidine in Myc-driven tumourigenesis
File(s)
Author(s)
Gjelaj, Ersa
Type
Thesis
Abstract
The MYC oncogene reprograms cellular metabolism to fulfil the biosynthetic demands of cancer cells. A key aspect of this process involves the uptake of essential amino acids through the L-type amino acid transporter (LAT1), which is crucial for MYC-driven glutamine metabolism and tumour formation. LAT1 is an obligate antiporter, transporting amino acids across the membrane by exchanging an intracellular amino acid for an extracellular one. Given that glutamine, a bidirectional LAT1 substrate, serves as a primary fuel for the Krebs cycle, the heightened demand for glutamine in MYC-driven cancer cells could impact LAT1 function. Identifying how MYC-transformed cells maintain LAT1 activity during extensive glutamine catabolism could unveil potential metabolic vulnerabilities. This research reveals histidine as the primary bidirectional LAT1 substrate in Myc-driven mammary tumour cells and emphasizes the essential role of histidine in maintaining amino acid homeostasis. Our results demonstrate that Myc-driven mammary tumours exhibit increased histidine levels and uptake, influenced by glutamine availability. We show that histidine availability sustains LAT1-transport activity, mTORC1/4EBP1 signalling, and protein translation, providing Myc-driven tumour cells with a proliferative advantage. Under histidine scarcity, Myc- and Atf4-dependent upregulation of specific amino acid transporters, including Lat1, maintains essential amino acid levels and supports proliferation. We establish that histidine contributes to Myc-driven tumour growth and propose that dietary histidine restriction could be a viable treatment strategy on its own or in combination with other drugs. Together, these results identify histidine availability as a metabolic vulnerability in glutamine-addicted cancers and underscore its important role in maintaining amino acid homeostasis in Myc-driven cancer cells.
Version
Open Access
Date Issued
2024-09-29
Date Awarded
2025-06-01
Copyright Statement
Attribution-NonCommercial-ShareAlike 4.0 International Licence (CC BY NC-SA)
Advisor
Yuneva, Mariia
Publisher Department
Department of Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)